The present invention relates to a novel agent for prophylaxis or treatment of inflammatory bowel diseases, more particularly an agent for prophylaxis or treatment of inflammatory bowel diseases which comprises as an active ingredient sulfodehydroabietic acid or a pharmaceutically acceptable salt thereof, and a use of said active ingredient in preparation of an agent for prophylaxis or treatment of inflammatory bowel diseases, and further relates to a method for prophylaxis or treatment of inflammatory bowel diseases.
Inflammatory bowel diseases include intractable inflammatory diseases of large and small intestines which are caused by various nosogenesis, for example, ulcerative colitis which is a cryptogenic diffuse non-specific inflammation wherein mucosa on the large intestine is mainly invaded and erosion and ulcer are formed, or Crohn""s disease which is a cryptogenic non-specific granulomatous inflammatory disease accompanied by fibrosis or ulcer. In addition, the lesion of the intestine in Behxc3xa7et""s disease which is a chronic systemic inflammatory disease is also included.
The nosogenesis of ulcerative colitis, Crohn""s disease, or Behxc3xa7et""s disease has not been clarified yet, but their immunological mechanisms have recently attracted a lot of attentions. In the medication of these inflammatory bowel diseases, immunosupressants, steroids, salazosulfapyridine, etc. have been used, but they cannot exhibit sufficient effects in certain patients. Besides, they should be improved with respect to side effects, and under these circumstances, it has been desired to develop a medicament being more effective and having a high safety.
On the other hand, sulfodehydroabietic acid or a salt thereof has been known to exhibit an inhibitory activity of acid secretion or pepsin secretion, etc., and to be useful as an agent for prophylaxis or treatment of peptic ulcer (gastric ulcer, duodenal ulcer) or gastritis (JP-A-58-77814, JP-A-63-165361, JP-A-2-167258). It is considered that peptic ulcer (gastric ulcer, duodenal ulcer) or gastritis and inflammatory bowel diseases are different in not only their lesion regions, but also their nosogenesis is quite different. In the nosogenesis of peptic ulcer such as gastric ulcer and duodenal ulcer, the digestion by gastric juice cannot be left out of consideration. In the medication of these diseases, a medicament exhibiting an inhibitory activity of acid secretion such as a histamine H2 receptor antagonist or a proton pump inhibitor is mainly used in the medication of peptic ulcer and gastritis. On the other hand, an immunosupressant, a steroid, a salazosulfapyridine, etc. is mainly employed in the medication of inflammatory bowel diseases, which is quite different from the medication of peptic ulcer or gastritis.
It has not been known at all that sulfodehydroabietic acid or a salt thereof is useful in the prophylaxis or treatment of inflammatory bowel diseases.
An object of the present invention is to provide a novel agent being useful in the prophylaxis or treatment of inflammatory bowel diseases.
During the studies on a novel remedy for inflammatory bowel diseases, the present inventors have found that sulfodehydroabietic acid disclosed in JP-A-58-77814, JP-A-63-165361, etc. or a pharmaceutically acceptable salt thereof exhibits an excellent effect in the prophylaxis or treatment of inflammatory bowel diseases, and have accomplished the present invention.
That is, the present invention provides an agent for prophylaxis or treatment of inflammatory bowel diseases, which comprises as an active ingredient sulfodehydroabietic acid (chemical name: (+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a-octadehydro-1,4a-dimethyl-7-(1-methylethyl)-6-sulfo-1-phenanthrenecarboxylic acid) of the following formula (I): 
or a pharmaceutically acceptable salt thereof.
The present invention also relates to a use of said sulfodehydroabietic acid (I) or a pharmaceutically acceptable salt thereof in preparation of an agent for prophylaxis or treatment of inflammatory bowel diseases.
Moreover, the present invention provides a method for prophylaxis or treatment of inflammatory bowel diseases which comprises administering said sulfodehydroabietic acid (I) or a pharmaceutically acceptable salt thereof orally or parenterally to a patient being suffering from an inflammatory bowel disease.
The active ingredient of the present agent for prophylaxis or treatment of inflammatory bowel diseases, sulfodehydroabietic acid of the formula (I) or a pharmaceutically acceptable salt thereof, is a known compound, and can be prepared, for example, by the methods disclosed in JP-A-58-77814, JP-A-63-165361, JP-A-2-167258, or by a modified method thereof.
The pharmaceutically acceptable salt of sulfodehydroabietic acid of the formula (I) includes, for example, a salt with an alkali metal (e.g., sodium, lithium, potassium, etc.), a salt with an alkaline earth metal (e.g., magnesium, calcium, etc.), and a salt with a metal such as aluminum. Among them, the preferable salt is a sodium salt of sulfodehydroabietic acid, especially a monosodium salt or a disodium salt thereof, and the most preferable salt is sulfodehydroabietic acid monosodium salt. Sulfodehydroabietic acid monosodium salt is more advantageous than disodium salt thereof as being less hygroscopic and being more stable (JP-A-63-165361). Besides, a pharmaceutically acceptable salt of sulfodehydroabietic acid may exist as well in the form of a hydrate thereof, and the hydrate of sulfodehydroabietic acid monosodium salt may be, for example, pentahydrate thereof, i.e., sulfodehydroabietic acid monosodium salt pentahydrate. The monosodium salt pentahydrate of sulfodehydroabietic acid of the formula (I) (chemical name: (+)-(1R,4aS,10aR)-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-6-sulfo-1-phenanthrenecarboxylic acid 6-sodium salt pentahydrate) has been known as Ecabet sodium.
According to the study of the present inventors, sulfodehydroabietic acid (I) or a pharmaceutically acceptable salt thereof of the active ingredient is hardly absorbed at the gut, and when it is administered orally, it can efficiently reach to the inferior gut and can adhere to the mucosa of the lesion site, and exhibit the pharmacological effects thereof so that the efficacy thereof is extremely excellent. In addition, sulfodehydroabietic acid (I) or a pharmaceutically acceptable salt thereof of the active ingredient shows few side effects, and the safety thereof is extremely high.
The agent for prophylaxis or treatment of inflammatory bowel diseases of the present invention is effective on the lesion of the intestine (including fistula) in Crohn""s disease, the lesion of the intestine in Behxc3xa7et""s diseases, ulcerative colitis, hemorrhagic rectal ulcer, ileum pouchitis, etc.
Besides, since sulfodehydroabietic acid (I) or a pharmaceutically acceptable salt thereof of the active ingredient of the present invention can cure the lesion of the gut without causing a stenosis, it may also be useful in the prophylaxis of the stenosis of the gut, especially in the prophylaxis of the stenosis of the intestine accompanying with inflammatory bowel diseases. When surgically treating a patient of an inflammatory bowel disease, an artificial anus may be constructed, but in said patient, such an inflammation may occasionally spread to the periphery of the artificial anus. The sulfodehydroabietic acid (I) or a pharmaceutically acceptable salt thereof of the active ingredient of the present invention is also effective in the inflammation of artificial anus periphery.
The sulfodehydroabietic acid (I) or a pharmaceutically acceptable salt thereof of the active ingredient of the present invention may be administered either orally or rectally, and further can be administered directly into the intestine through an artificial anus in a patient having one, or can directly be applied in the inflammation of the periphery of ane artificial anus.
The present agent for prophylaxis or treatment of inflammatory bowel diseases can be used in the form of oral preparation, intra-intestinal infusion preparation, suppository preparation, or external preparation, which should be selected according to the administration routes. Oral preparation may be solid preparations such as tablets, capsules, powders, granules, or liquid preparation such as solutions, suspension, etc. A preparation being suitable for oral administration may contain a pharmaceutically acceptable carrier or excipient. A pharmaceutically acceptable carrier or excipient being suitable for a solid preparation such as tablets or capsules may be, for example, binders (e.g., acacia, gelatin, dextrin, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone), diluents (e.g., lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate, crystalline cellulose), lubricants (e.g., magnesium stearate, calcium stearate, stearic acid, talc, anhydrous silicic acid), disintegrants (e.g., corn starch, potato starch, carboxymethylcellulose, carboxymethylcellulose calcium, alginic acid), and wetting agents (e.g., sodium laurylsulfate). A pharmaceutically acceptable carrier or excipient being suitable for a liquid preparation such as solutions or suspensions may be, for example, aqueous vehicles (e.g., water), suspending agents (e.g., acacia, gelatin, methyl cellulose, carboxymethylcellulose sodium, hydroxymethylcellulose, aluminum stearate gel), surfactants (e.g., lecithin, sorbitan monooleate, glycerin monostearate), and non-aqueous vehicles (e.g., glycerin, propylene glycol, vegetable oil). Moreover, liquid preparations may contain preservatives (e.g., p-hydroxybenzoic acid methyl ester, p-hydroxybenzoic acid propyl ester), flavors, and/or coloring agents.
The intra-intestinal infusion (enema) preparation may be in the form of aqueous solution or suspension using the above-mentioned aqueous vehicles or suspending agents. If necessary, the intra-intestinal infusion preparation may be in the form of sol or gel preparation using a thickening agent such as polyacrylic acid, gelatin, etc.
The suppository may be ones which are prepared by mixing the active ingredient of the formula (I) or a pharmaceutically acceptable salt thereof with a commercially available oily base such as Witepsole, etc., or a water-soluble base such as macrogol, glycerogelatin, etc. by a conventional method, and may be in the form of capsule-type suppository, tablet-type suppository, or ointment-type suppository.
The external preparation may include external powder preparations, ointments, creams, etc.
In the present specification, the term xe2x80x9cprophylaxis or treatmentxe2x80x9d comprises the improvement of symptoms, the prevention of exacerbation, the maintainance of remission, the prevention of recrudescence, the prevention of the stenosis of the gut, and more comprises the prevention of recrudescence after surgical operation and the prevention of the stenosis of the operated region.
The dose of the compound (I) or a pharmaceutically acceptable salt thereof of the active ingredient of the present agent may vary according to the administration route, age, weight or conditions of a patient, or severity of the disease to be cured, but the daily dose thereof for an adult is usually in the range of about 10 mg to 300 mg/kg, preferably in the range of about 20 mg to 300 mg/kg, especially in the range of 50 mg /kg to 200 mg/kg.
In the present specification, the inflammatory bowel diseases mean not only inflammatory bowel disease in a strict sense such as Crohn""s disease, ulcerative colitis, but also inflammatory bowel disease in a broad sense including the lesion of the intenstine accompanying with Behxc3xa7et""s disease, hemorrhagic rectal ulcer, ileum pouchitis, intestinal tuberculosis, ischemic enteritis, drug-induced colitis, radiation enteritis, infective enteritis, etc.